Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/08—Vasodilators for multiple indications
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to new therapeutic applications involving the following class of compounds of formula I:
• R 1 , R 2 and R 3 are the same or different and signify hydrogens, halogens, alkyl, alkylaryl, alkyloxy, hydroxy, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group;
• R 4 signifies hydrogen, alkyl or alkylaryl group;
• X signifies CH 2 , oxygen atom or sulphur atom;
• n is 1, 2 or 3, with the proviso that when n is 1, X is not CH 2 ; and the individual (R)- and (S)-enantiomers or mixtures of enantiomers and pharmaceutically acceptable salts thereof;
• alkyl means hydrocarbon chains, straight or branched, containing from one to six carbon atoms, optionally substituted by aryl, alkoxy, halogen, alkoxycarbonyl or hydroxycarbonyl groups;
• aryl means a phenyl or naphthyl group, optionally substituted by alky
• Particular compounds of formula I include: (S)-5-(2-aminoethyl)-l-(l,2,3,4- tetrahydronaphthalen-2-yl)- 1 ,3-dihydroimidazole-2-thione; (S)-5-(2-aminoethyl)- 1 -(5,7- difluoro-l,2,3,4-tetrahydronaphthalen-2-yl)-l,3-dihydroimidazole-2-thione; (R)-5-(2- aminoethyl)-l-chroman-3-yl-l,3-dihydroimidazole-2-thione; (R)-5-(2-aminoethyl)-l-(6- hydroxychroman-3-yl)-l,3-dihydroimidazole-2-thione; (R)-5-(2-aminoethyl)-l-(8- hydroxychroman-3-yl)-l,3-d
• the invention relates to drug combinations involving the following specific salts of compounds of formula I: (S)-5-(2-aminoethyl)-l -(1,2,3,4- tetrahydronaphthalen-2-yl)-l ,3-dihydroimidazole-2-thione hydrochloride; (S)-5-(2- aminoethyl)-l-(5,7-difluoro-l,2,3,4-tetrahydronaphthalen-2-yl)-l,3-dihydroimidazole-2- thione hydrochloride; (R)-5-(2-aminoethyl)- 1 -chroman-3-yl- 1 ,3-dihydroimidazole-2- thione hydrochloride; (R)-5-(2-aminoethyl)-l-(6-hydroxychroman-3-yl)-l,3- dihydroimidazole-2-thione hydrochloride; (R))
• the invention relates to the use of the following specific compound of formula I: (R)-5-(2-aminoethyl)-l-(6,8-difluorochroman-3-yl)-l,3-dihydroimidazole-2- thione and pharmaceutically acceptable salts thereof, especially the hydrochloride salt.
• the term treatment and variations such as 'treat' or 'treating' refer to any regime that can benefit a human or non-human animal.
• the treatment may be in respect of an existing condition or may be prophylactic (preventative treatment).
• Treatment may include curative, alleviation or prophylactic effects.
• the treatment may also involve curing, alleviating or preventing symptoms associated with the disorder rather than acting on the underlying cause of the disorder.
• the compounds of the present invention may cure, alleviate or prevent changes in body temperature, flushing, palpitations, etc.
• the invention relates to the following therapeutic applications of these compounds: treatment of congestive heart failure, treatment of angina, treatment of arrhythmias, treatment of circulatory disorders such as Raynaud's Phenomenon (sometimes known as "Raynaud's Disease”), treatment of migraine, and treatment of anxiety and anxiety disorders.
• the invention includes the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating congestive heart failure.
• the invention includes the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating angina.
• the invention includes the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating arrhythmias.
• the invention includes the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating circulatory disorders such as Raynaud's Phenomenon (sometimes known as "Raynaud's Disease").
• the invention includes the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating migraine.
• the invention includes the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating anxiety disorders.
• the invention also includes a method of treating one or more of the conditions mentioned above comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof.
• the compounds of formula I or their pharmaceutically acceptable salts may be formulated into a pharmaceutical composition.
• composition may further comprise another active pharmaceutical ingredient.
• active ingredients are described in PCT/PT2007/000002.
• composition may also comprise suitable a pharmaceutically acceptable excipient and/or pharmaceutically acceptable carrier.
• nepicastat 1 (the reference compound) produced a concentration-dependent decrease in the ⁇ -hydroxylation of dopamine with IC50 values in the low nM range against human D ⁇ H activity (see Table 2).
• Compound 4 was chosen for further in vivo studies, being the compound most closely related to nepicastat 1 in order to provide conclusive evidence that the structural modifications made to the molecule as part of the present invention are responsible for the surprisingly markedly improved biological properties observed.
• both 4 and 1 reduced noradrenaline levels in a dose-dependent manner in left ventricle.
• the maximal inhibitory effect was attained at a dose of 100 mg/kg.
• Figure 1 is a graph showing the time-dependent decrease of noradrenaline levels in the left ventricle of mice treated orally with 100 mg/kg of 4 or nepicastat 1. Symbols are means of 5 determinations per group; vertical lines indicate S.E.M.
• Figure 2 is two graphs showing noradrenaline levels in the mouse left ventricle and brain parietal cortex 9 h after oral administration of 4 or nepicastat 1. Symbols are means of 5 determinations per group; vertical lines indicate S.E.M.
• Figure 3 is four graphs showing noradrenaline levels in the rat heart (left atrium and left ventricle) and brain (frontal and parietal cortex) 9 h after the oral administration of 4 or nepicastat 1. Columns are means of 5 determinations per group; vertical lines indicated S.E.M.
• Some compounds of general formula I are very potent dopamine- ⁇ -hydroxylase inhibitors and have potentially valuable pharmaceutical properties in the treatment of some cardiovascular disorders, where a reduction in the enzymatic hydroxylation of dopamine to noradrenaline may be of therapeutic benefit, such as hypertension and chronic heart failure.
• a reduction in the enzymatic hydroxylation of dopamine to noradrenaline may be of therapeutic benefit, such as hypertension and chronic heart failure.
• CNS brain

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• Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Epidemiology (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Urology & Nephrology (AREA)
• Vascular Medicine (AREA)
• Hospice & Palliative Care (AREA)
• Pain & Pain Management (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Applications Claiming Priority (2)

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• 2007
  • 2007-01-12 GB GBGB0700635.6A patent/GB0700635D0/en not_active Ceased
• 2008
  • 2008-01-10 JP JP2009545511A patent/JP2010515726A/ja active Pending
  • 2008-01-10 KR KR1020097016624A patent/KR20090100443A/ko not_active Application Discontinuation
  • 2008-01-10 BR BRPI0806514-4A patent/BRPI0806514A2/pt not_active IP Right Cessation
  • 2008-01-10 WO PCT/PT2008/000001 patent/WO2008085074A2/en active Application Filing
  • 2008-01-10 US US12/522,525 patent/US20100286219A1/en not_active Abandoned
  • 2008-01-10 CA CA002674305A patent/CA2674305A1/en not_active Abandoned
  • 2008-01-10 CN CNA2008800020370A patent/CN101600474A/zh active Pending
  • 2008-01-10 RU RU2009130726/15A patent/RU2009130726A/ru unknown
  • 2008-01-10 EP EP08705171A patent/EP2111262A2/en not_active Withdrawn
  • 2008-01-10 AU AU2008204006A patent/AU2008204006A1/en not_active Abandoned
  • 2008-01-10 MX MX2009007329A patent/MX2009007329A/es not_active Application Discontinuation
  • 2008-01-11 AR ARP080100134A patent/AR064869A1/es unknown

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